Despite the demonstration of numerous gene dosage effects associated with chromosome imbalance (aneuploidy), the relationship of these effects to the deleterious phenotypic abnormalities caused by aneuploidy is unknown. One site at which altered gene product concentrations could have profound effects is the plasma membrane. It is thus of interest that two phenomena involving plasma membrane receptors are altered in cells from individuals with trisomy 21 (Down Syndrome) to an extent exceeding that anticipated on the basis of gene dosage effects. Response to interferon involves a membrane receptor coded for by chromosome 21. However, trisomy 21 fibroblasts are approximately 5 times more sensitive to interferon than are diploid controls, as measured by the antiviral response. We will attempt to determine the step or steps at which this amplication of the gene dosage effect occurs by comparing trisomy 21, diploid and monosomy 21 human fibroblasts for three intermediates involved in the response to intereferon:(2'-5')oligoisoadenylate synthetase E, its product, (2'-5')oliogoisoadenylate, and protein kinase, PK-i. The induction of cAMP synthesis by Beta-adrenergic hormones is also enchanced 5 to 10-fold in trisomy 21 fibroblasts compared to controls. It is not known what component or components of this system are coded for by chromosome 21. We will therefore compare trisomic, diploid, and monosomic cells with respect to Beta-adrenergic receptors, methylation of membran phospolipids, adenylate cyclase, and the coupling protein, N. If these results suggest the receptors are coded for by chromosome 21, we will investigate this directly using interspecific hybrid mapping techniques. Experiments parallel to those described above will be performed with a mouse model system utilizing trisomy for chromosome 16, when such experiments appear warranted either by the value of comparative studies or because experiments can be carried out with mouse material that are not possible with humans. These studies are directly relevant to the developmental and potential clinical implications of the interferon and Beta-adrenergic systems in trysomy 21. They will also provide model systems for other membrane receptor mediated processes that may be involved in the phenotypic effects of aneuploidy.